1. Field of the Invention
This invention relates to a process for preparing an o-alkylated rapamycin derivative of high purity and also to an o-alkylated rapamycin derivative prepared by the process.
2. Description of the Related Art
Rapamycin is a macrolide antibiotic produced from Streptomyces hygroscopicus. It has been reported that rapamycin has immunosuppressive action and also has anticancerous and antifungal activities. Because of these useful pharmaceutical activities, much has been reported about rapamycin derivatives (see Drugs of Future 1999, 24(1): 22 to 29).
On the other hand, for the synthesis of rapamycin derivatives, there has been disclosed, for example, in WO94/09010, a process of preparing an o-alkylated rapamycin derivative by reaction between rapamycin and an alkyl triflate in toluene solvent in the presence of lutidine. In WO94/09010, no mention is made of the yield or purity of the resulting o-alkylated rapamycin derivative. We made an additional test, with the result that the yield was as low as 23% and the purity was at about 92 to 95%.
A process of synthesizing an o-alkylated rapamycin derivative improved by us has been proposed in US2005/0192311A1. In US2005/0192311A1, a process is disclosed wherein rapamycin and an alkyl triflate are reacted in methylene chloride solvent in the presence of N,N-diisopropylamine and the compound obtained by the reaction is purified by a normal phase chromatograph. Although the yield could be remarkably improved according to the process of US2005/0192311A1, the purity of the resulting o-alkylated rapamycin was as low as about 95% (see Comparative Example of this specification).
In general, the purity of drugs may be a very important factor with respect to relative merits for use as a bulk drug powder. Low purity indicates that a large amount of impurities are contained, and is judged as having a low reliability from aspects of medical efficacy and safety. In case those having such a low impurity are used as a bulk drug powder, identification and quantitative determination of impurities and safety tests of impurities have been needed, with the attendant problem of increasing a risk and cost of development. Accordingly, it is very advantageous in product development to obtain a bulk drug powder of high purity.